Study wrapper · #844
Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis.
Editor's note
This is a major, GRADE-rated network meta-analysis — 262 RCTs, 99,791 participants, 19 drugs — and it puts both tracked peptides at the center of the obesity-pharmacotherapy map. With moderate-to-high certainty, tirzepatide showed the largest one-year weight loss (−14.9% vs lifestyle), with subcutaneous and oral semaglutide also substantial (−9.8% and −10.9%). Crucially, subcutaneous semaglutide was the only drug associated with reduced all-cause mortality and myocardial infarction, and both semaglutide and tirzepatide were associated with lower heart-failure risk — though the mortality/MI estimates are driven by cardiovascular-outcome trials in high-risk populations, an important scoping caveat. The analysis is admirably balanced on harms: larger weight loss generally came with more discontinuation and gastrointestinal events, and tirzepatide, while cutting fat mass most (−25.7%), also cut lean mass most (−8.3%) — a real signal on muscle loss. No drug meaningfully improved quality of life. This is high-quality synthesis and among the most useful single references for weighting these peptides. Read the benefit and harm columns together.
Plain-language abstract
This large, carefully-rated analysis combined 262 randomized trials with nearly 100,000 people to compare 19 different weight-loss drugs in adults with overweight or obesity. Over one year, tirzepatide produced the greatest average weight loss (about 15%), with semaglutide (both the oral and injected forms) also producing large reductions (about 10-11%). Beyond weight, injected semaglutide was the only drug linked to a lower risk of death from any cause and of heart attack, and both semaglutide and tirzepatide were linked to lower heart-failure risk — though these heart benefits came largely from trials in people already at high heart risk. The analysis was even-handed about downsides: drugs causing more weight loss also tended to cause more stomach side effects and more people quitting. Notably, tirzepatide reduced body fat the most but also reduced muscle mass the most. None of the drugs clearly improved quality of life. The authors conclude that choosing a drug means weighing benefits against harms together with each patient.